Viruses are implicated in a variety of animal and human diseases. Numerous approaches have been proposed to combat these pathogens which include, but are not limited to, herpesviruses 1 and 2 (HSV-1 and HSV-2), influenza viruses A, B and C (orthomyxoviruses), parainfluenza viruses 1-4, mumps virus (paramyxovirus), adenoviruses, respiratory syncytial virus, Epstein-Barr virus, rhinoviruses, human immunodeficiency viruses (HIV), polioviruses, coxsackieviruses, echoviruses, rubella virus, varicella-zoster virus, neurodermotropic virus, variola virus, cytomegalovirus, hepatitis A, B and non-A, non-B viruses, papoviruses and rabies virus.
One approach in the development of antiviral compounds has been to identify compounds which interfere with the normal viral metabolism of nucleosides. Because the structures of these compounds are usually closely related to nucleosides which occur naturally in the mammalian host, few have good activity against the virus without untoward side effects. Some of the few compounds having activity are very expensive to produce. Thus, there is a continuing need for new compounds which act to kill viruses, to inhibit viral replication or to block the pathogenic actions of viruses.
The following references disclose various carbocyclic analogs of nucleosides:
Ichikawa, et al., European Patent Application No. EP0330992, published Sep. 9, 1989, discloses 2-hydroxy-3-hydroxymethylcyclobutyl substituted purines and pyrimidines having antiviral activity; PA1 Zahler, et al., European Patent Application No. EP0322854, published Jul. 5, 1989, discloses 2-hydroxy-3-hydroxymethylcyclobutyl substituted purines and pyrimidines having antiviral activity; PA1 Slusarchyk, et al., European Patent Application No. EP0335355, published Oct. 4, 1989, discloses 2,3-bis(hydroxymethyl)cyclobutyl substituted purines and pyrimidines having antiviral activity; PA1 Tolman, et al., U.S. Pat. No. 4,782,062, issued Nov. 1, 1988, discloses 9-((Z)-2-(hydroxymethyl)cyclobutylmethyl)guanine as a viral thymidine kinase inhibitor; PA1 Kjellin, et al., U.S. Pat. No. 4,644,001, issued Feb. 17, 1987, and U.S. Pat. No. 4,548,818, issued Oct. 22, 1985, disclose cyclopropyl-, cyclobutyl- and cyclopentyl-substituted purine analogs which are useful for treating obstructive airway disease or cardiac disease; PA1 Maccoss, et al., European Patent Application No. EP0184473, published Jun. 11, 1986, discloses 2-amino-9-((2)-2-(benzoyloxymethyl)cyclobutylmethyl)-6-benzoylpurine; PA1 Albrecht, et al., U.S. Pat. No. 3,923,792, issued Dec. 2, 1975, discloses cyclopropyl-, cyclopropylmethyl- and cyclopentyl-substituted cytosine analogs which are useful as antibacaterial agents; PA1 Albrecht, et al., U.S. Pat. No. 4,016,267, issued Apr. 5, 1977, discloses cyclopropyl-, cyclopropylmethyl- and cyclopentyl-substituted nucleoside analogs which are useful as antibacaterial agents; PA1 Ashton, et al., U.S. Pat. No. 4,617,304, issued Oct. 14, 1986, discloses ((hydroxymethylcyclopropyl)methyl)-substituted purine and pyrimidine analogs as antiviral agents; PA1 Temple, et al., J. Med. Pharm. Chem. 5 866 (1962), discloses cyclopropyl-substituted purine analogs which are useful for treating human epidermal carcinoma; PA1 Masoliver, et al., C.A. 107:236375e, Spanish Patent No. ES519898, published Mar. 16, 1984, discloses cyclopropylmethyl-substituted purine analogs; and PA1 Marquez, et al., Medicinal Research Reviews, 6 1-40 (1986) discloses substituted-cyclopentyl nucleoside analogs. PA1 Q is --OH, --SH, alkoxy, thioalkoxy, halogen, ##STR7## wherein m is 1 to 5, --NR.sub.1 R.sub.2 wherein R.sub.1 and R.sub.2 are as defined above, or --NHC(O)R.sub.3 wherein R.sub.3 is as defined above; and PA1 T is hydrogen, C.sub.1 to C.sub.10 alkyl, 2-haloethyl, halomethyl, difluoromethyl, trifluoromethyl, halogen, cyano, nitro, vinyl, 2-halovinyl, alkynyl, hydroxmethyl, formyl, azidomethyl, 2-hydroxyethyl, --NR.sub.1 R.sub.2 wherein R.sub.1 and R.sub.2 are as defined above, --NHOH, --SH, propenyl, 3,3,3-trifluoropropenyl, 2-(alkoxycarbonyl)ethenyl, 2-cyanoethenyl, ##STR8## wherein m is 1 to 5, or --CH.sub.2 NR.sub.2 R.sub.2 wherein R.sub.1 and R.sub.2 are as defined above; and PA1 wherein E is hydrogen, --CH.sub.2 OH or --OH; and PA1 G and D are independently selected from hydrogen, C.sub.1 to C.sub.10 alkyl, --OH, --CH.sub.2 OH, --CH.sub.2 OR.sub.20 wherein R.sub.20 is C.sub.1 to C.sub.6 alkyl, --CH.sub.2 OC(O)R.sub.21 wherein R.sub.21 is C.sub.1 to C.sub.10 alkyl, --CH.sub.2 OC(O)CH(R.sub.22)(NHR.sub.23) wherein R.sub.22 is the side chain of any of the naturally occurring amino acids and R.sub.23 is hydrogen or --C(O)CH(R.sub.24)(NH.sub.2) wherein R.sub.24 is the side chain of any of the naturally occurring amino acids, --CH.sub.2 SH, --CH.sub.2 Cl, --CH.sub.2 F, --CH.sub.2 Br, --CH.sub.2 I, --C(O)H, --CH.sub.2 CN, --CH.sub.2 N.sub.3, --CH.sub.2 NR.sub.1 R.sub.2, --CO.sub.2 R.sub.1, --CH.sub.2 CH.sub.2 OH, --CH.sub.2 CH.sub.2 OR.sub.20 wherein R.sub.20 is as defined above --CH.sub.2 CH.sub.2 OC(O)R.sub.21 wherein R.sub.21 is as defined above, --CH.sub.2 CH.sub.2 OC(O)CH(R.sub.22)(NHR.sub.23) wherein R.sub.22 and R.sub.23 are as defined above, --CH.sub.2 CH.sub.2 PO.sub.3 H.sub.2, --CH.sub.2 OPO.sub.3 H.sub.2, --OCH.sub.2 PO.sub.3 H.sub.2 and --CH.sub.2 CO.sub.2 R.sub.3 wherein R.sub.1, R.sub.2 and R.sub.3 are as defined above, with the proviso that when E is --OH then D is not --OH and with the proviso that when E is hydrogen and D is hydrogen or C.sub.1 to C.sub.10 alkyl then G is not hydrogen or C.sub.1 to C.sub.10 alkyl; or a pharmaceutically acceptable salt thereof. PA1 Q is --OH, --SH, alkoxy, thioalkoxy, halogen, ##STR13## wherein m is 1 to 5, --NR.sub.1 R.sub.2 wherein R.sub.1 and R.sub.2 are as defined above, --NHC(O)R.sub.3 wherein R.sub.3 is as defined above; and PA1 T is hydrogen, C.sub.1 to C.sub.10 alkyl, 2-haloethyl, halomethyl, difluoromethyl, trifluoromethyl, halogen, cyano, nitro, vinyl, 2-halovinyl, alkynyl, hydroxmethyl, formyl, azidomethyl, 2-hydroxyethyl, --NR.sub.1 R.sub.2 wherein R.sub.1 and R.sub.2 are as defined above, --NHOH, --SH, propenyl, 3,3,3-trifluoropropenyl, 2-(alkoxycarbonyl)ethenyl, 2-cyanoethenyl, ##STR14## wherein m is 1 to 5, or --CH.sub.2 NR.sub.1 R.sub.2 wherein R.sub.1 and R.sub.2 are as defined above. PA1 G and D are independently selected from hydrogen, C.sub.1 to C.sub.10 alkyl, --OH, --OR.sub.11, --CH.sub.2 OH, --CH.sub.2 OR.sub.11, --CH.sub.2 OC(O)R.sub.21 wherein R.sub.21 is as defined above, --CH.sub.2 OC(O)CH(R.sub.22)(NHR.sub.23) wherein R.sub.22 and R.sub.23 are as defined above, --CH.sub.2 SH, --CH.sub.2 Cl, --CH.sub.2 F, --CH.sub.2 Br, --CH.sub.2 I, --C(O)H, --CH.sub.2 CN, --CH.sub.2 N.sub.3, --CH.sub.2 NR.sub.12 R.sub.2, --CO.sub.2 R.sub.1, --CH.sub.2 CH.sub.2 OH, --CH.sub.2 CH.sub.2 OR.sub.11, --CH.sub.2 CH.sub.2 OC(O)R.sub.21 wherein R.sub.21 is as defined above, --CH.sub.2 CH.sub.2 OC(O)CH(R.sub.22)(NHR.sub.23) wherein R.sub.22 and R.sub.23 are as defined above, --CH.sub.2 OPO.sub.3 H.sub.2, --CH.sub.2 CH.sub.2 PO.sub.3 H.sub.2, --CH.sub.2 PO.sub.3 H.sub.2, --OCH.sub.2 PO.sub.3 H.sub.2 and --CH.sub.2 CO.sub.2 R.sub.3 wherein R.sub.12 is hydrogen, C.sub.1 to C.sub.10 alkyl, R.sub.3 is hydrogen, C.sub.1 to C.sub.10 alkyl, carboxyalkyl or aminoalkyl, R.sub.11 is C.sub.1 to C.sub.6 alkyl or a hydroxy protecting group, and R.sub.13 is hydrogen or an N-protecting group; with the proviso that when E is --OH then D is not --OH. PA1 G and D are independently selected from hydrogen, C.sub.1 to C.sub.10 alkyl, --OH, --OR.sub.11, --CH.sub.2 OH, --CH.sub.2 OR.sub.11, --CH.sub.2 OC(O)R.sub.21 wherein R.sub.21 is as defined above, --CH.sub.2 OC(O)CH(R.sub.22)(NHR.sub.23) wherein R.sub.22 and R.sub.23 are as defined above, --CH.sub.2 SH, --CH.sub.2 Cl, --CH.sub.2 F, --CH.sub.2 Br, --CH.sub.2 I, --C(O)H, --CH.sub.2 CN, --CN.sub.2 N.sub.3, --CH.sub.2 NR.sub.12 R.sub.2, --CO.sub.2 R.sub.1, --CH.sub.2 CH.sub.2 OH, --CH.sub.2 CH.sub.2 OR.sub.11, --CH.sub.2 CH.sub.2 OC(O)R.sub.21 wherein R.sub.21 is as defined above, --CH.sub.2 CH.sub.2 OC(O)CH(R.sub.22)(NHR.sub.23) wherein R.sub.22 and R.sub.23 are as defined above, --CH.sub.2 OPO.sub.3 H.sub.2, --CH.sub.2 CH.sub.2 PO.sub.3 H.sub.2, --CH.sub.2 PO.sub.3 H.sub.2, --OCH.sub.2 PO.sub.3 H.sub.2 and --CH.sub.2 CO.sub.2 R.sub.3 wherein R.sub.12 is hydrogen, C.sub.1 to C.sub.10 alkyl or an N-protecting group, R.sub.2 is hydrogen or C.sub.1 to C.sub.10 alkyl, R.sub.3 is hydrogen, C.sub.1 to C.sub.10 alkyl, carboxylakyl or aminoalkyl, R.sub.11 is C.sub.1 to C.sub.6 alkyl or a hydroxy protecting group, and R.sub.13 is an N-protecting group; PA1 R.sub.16 is hydrogen, --NH.sub.2 or --OH; PA1 R.sub.17 is --OH or halogen; and PA1 R.sub.18 is --NO.sub.2 or --NH.sub.2 ; with the proviso that when E is --OH then D is not --OH. PA1 G and D are independently selected from hydrogen, C.sub.1 to C.sub.10 alkyl, --OH, --OR.sub.11, --CH.sub.2 OH, --CH.sub.2 R.sub.11, --CH.sub.2 OC(O)R.sub.21 wherein R.sub.21 is as defined above, --CH.sub.2 OC(O)CH(R.sub.22)(NHR.sub.23) wherein R.sub.22 and R.sub.23 are as defined above, --CH.sub.2 SH, --CH.sub.2 Cl, --CH.sub.2 F, --CH.sub.2 Br, --CH.sub.2 I, --C(O)H, --CH.sub.2 CN, --CH.sub.2 N.sub.3, --CH.sub.2 NR.sub.12 R.sub.2, --CO.sub.2 R.sub.1, --CH.sub.2 CH.sub.2 OH, --CH.sub.2 CH.sub.2 OR.sub.11, --CH.sub.2 CH.sub.2 OC(O)R.sub.21 wherein R.sub.21 is as defined above, --CH.sub.2 CH.sub.2 OC(O)CH(R.sub.22)(NHR.sub.23) wherein R.sub.22 and R.sub.23 are as defined above, --CH.sub.2 OPO.sub.3 H.sub.2, --CH.sub.2 CH.sub.2 PO.sub.3 H.sub.2, --CH.sub.2 PO.sub.3 H.sub.2, --OCH.sub.2 PO.sub.3 H.sub.2 and --CH.sub.2 CO.sub.2 R.sub.3 wherein R.sub.12 is hydrogen, C.sub.1 to C.sub.10 alkyl or an N-protecting group, R.sub.2 is hydrogen or C.sub.1 to C.sub.10 alkyl, R.sub.3 is hydrogen, C.sub.1 to C.sub.10 alkyl, carboxyalkyl or aminoalkyl, R.sub.11 is C.sub.1 to C.sub.6 alkyl or a hydroxy protecting group, and R.sub.13 is an N-protecting group; and PA1 R.sub.19 is C.sub.1 to C.sub.6 alkyl; with the proviso that when E is --OH then D is not --OH. PA1 G and D are independently selected from hydrogen, C.sub.1 to C.sub.10 alkyl, --OH, --OR.sub.11, --CH.sub.2 OH, --CH.sub.2 OR.sub.11, --CH.sub.2 OC(O)R.sub.21 wherein R.sub.21 is as defined above, --CH.sub.2 OC(O)CH(R.sub.22 (NHR.sub.23) wherein R.sub.22 and R.sub.23 are as defined above, --CH.sub.2 SH, --CH.sub.2 Cl, --CH.sub.2 F, --CH.sub.2 Br, --CH.sub.2 I, --C(O)H, --CH.sub.2 CN, --CH.sub.2 N.sub.3, --CH.sub.2 NR.sub.12 R.sub.2, --CO.sub.2 R.sub.1, --CH.sub.2 CH.sub.2 OH, --CH.sub.2 CH.sub.2 OR.sub.11, --CH.sub.2 CH.sub.2 OC(O)R.sub.21 wherein R.sub.21 is as defined above, --CH.sub.2 CH.sub.2 OC(O)CH(R.sub.22)(NHR.sub.23) wherein R.sub.22 and R.sub.23 are as defined above, --CH.sub.2 OPO.sub.3 H.sub.2, --CH.sub.2 CH.sub.2 PO.sub.3 H.sub.2, --CH.sub.2 PO.sub.3 H.sub.2, --OCH.sub.2 PO.sub.3 H.sub.2 and --CH.sub.2 CO.sub.2 R.sub.3 wherein R.sub.12 is hydrogen, C.sub.1 to C.sub.10 alkyl or an N-protecting group, R.sub.2 is hydrogen or C.sub.1 to C.sub.10 alkyl, R.sub.3 is hydrogen, C.sub.1 to C.sub.10 alkyl, carboxyalkyl or aminoalkyl, R.sub.11 is C.sub.1 to C.sub.6 alkyl or a hydroxy protecting group, and R.sub.13 is an N-protecting group; and PA1 T is hydrogen, C.sub.1 to C.sub.10 alkyl, 2-haloethyl, halomethyl, difluoromethyl, trifluoromethyl, halogen, cyano, nitro, vinyl, 2-halovinyl, alkynyl, hydroxmethyl, formyl, azidomethyl, 2-hydroxyethyl, --NR.sub.12 R.sub.2 wherein R.sub.12 and R.sub.2 are as defined above, --NHOH, --SH, propenyl, 3,3,3-trifluoropropenyl, 2-(alkoxycarbonyl)ethenyl, 2-cyanoethenyl, ##STR20## wherein m is 1 to 5, or --CH.sub.2 NR.sub.12 R.sub.2 wherein R.sub.12 and R.sub.2 are as defined above; with the proviso that when E is --OH then D is not --OH.